Big Boned: How Your Skeleton Can Make You Fat

Bones help fix themselves by controlling the body's metabolism.

THE STUDY “Endocrine Regulation of Energy Metabolism by the Skeleton” by Na Kyung Lee et al., published in Cell, August 10, 2007.

THE MOTIVE Nestled about the body, endocrine glands like the thyroid, ovaries, testes, kidneys, and the heart secrete hormones, controlling crucial processes like hunger, blood pressure, and sexual reproduction. Now a team of scientists has shown that even cells in the skeleton—which we commonly think of as mere scaffolding—exude a hormone that helps the body store fat and regulate sugar levels in the blood. The finding not only shatters suppositions about the skeletal system, but it may ultimately yield strategies for treating diabetes.

THE METHODS In 2000, Gerard Karsenty, a molecular geneticist at Columbia University in New York City, discovered that leptin, a hormone made by fat cells, helps mold and repair the skeleton by acting upon bone-building cells called osteoblasts. Because hormone signaling is usually a two-way street, Karsenty thought the skeleton might in turn influence the fat cells. To find out how, he turned to an engineered strain of mice lacking a gene for what was then a mysterious protein called osteocalcin, which is produced by osteoblasts. The mutant mice produced less insulin—the hormone made in the pancreas that helps cells burn sugar—and they were plump and diabetic, with high levels of glucose in their blood. (Osteocalcin’s role appears to involve regulating energy metabolism.)

Karsenty and his team then set about finding what other genes might be involved in this newfound signaling. They engineered other strains of mice, each lacking one of the other genes that are especially active in osteoblasts. The most intriguing mutant type of mice were unusually thin; they generated more active osteocalcin, secreted more insulin, and produced many times more of the insulin-releasing cells in the pancreas. They also created two to three times more adiponectin, a signaling molecule that enhances insulin sensitivity. All these factors protected them from developing diabetes and obesity—just the opposite of the osteocalcin-deficient mice.

In the next experiment, Karsenty looked for evidence of such signaling effects in osteoblasts from normal mice. When he put the osteoblasts on one side of a porous membrane with either insulin-releasing pancreas cells or insulin-sensitizing fat cells on the other side, the pancreas cells made more insulin, and the fat cells made more adiponectin. Osteoblasts taken from the osteocalcin-deficient mice, however, had no impact. This demonstrates, Karsenty says, that the osteoblast component of the skeletal system has a direct role in regulating energy metabolism in ordinary animals.

THE MEANING Why do bones produce a hormone that regulates sugar levels within the body? The answer, Karsenty says, lies deep in our evolutionary past. One of the functions of the skeleton (especially important before the advent of orthopedic surgery) is to repair broken bones. “But [this process] requires a lot of energy,” he says, “because you have to very quickly resorb the bone and replace it. For bone remodeling to work, you need to be tightly linked to energy metabolism.”

Karsenty’s findings could lead to new treatments for diabetes. Because osteocalcin levels in untreated patients with diabetes tend to be low, injections of the protein might alleviate the symptoms of diabetes in humans, an approach Karsenty is testing in mice. “The addition of osteocalcin as a metabolic regulator may one day lead to novel therapies, but we need to understand much better how it works and how it fits into physiology before such therapies can be attempted in humans,” says endocrinologist Mitch Lazar, director of the Institute for Diabetes, Obesity, and Metabolism at the University of Pennsylvania. Still, he says, “the Karsenty paper is first to show that the skeleton is an endocrine organ, which is exciting.”